Rifaximin is disclosed in U.S. Pat. No. 4,341,785, and is a non-aminoglycoside semi-synthetic, non-systemic antibacterial related to rifamycin. Chemically, rifaximin is designated as (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-{acute over (α)}]-benzimidazole-1,15(2H)-dione,25-acetate. Rifaximin is commercially available in the United States as tablets for oral administration under the trade name of Xifaxan® in dosage strengths of 200 mg and 550 mg. The dosage strength of 200 mg is indicated for the treatment of patients (≧12 years of age) with traveler's diarrhea caused by invasive strains of Escherichia coli and the dosage strength of 550 mg is indicated for the reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≧18 years of age.
As a drug can exist in various polymorphic forms with a significant difference in their pharmacological and toxicological properties along with variable bioavailabilities, it remains a challenge for a formulator to maintain the polymorphic integrity of the drug during the entire shelf-life of the drug, so that the end user consistently gets the same desired effect upon repeated administration. Also, it is required from the drug regulatory agencies to have the manufacturing methods of the drugs standardized and controlled in such a way that these give homogeneous results in terms of polymorphism. The importance of maintaining the same polymorphic form becomes high in cases where there is a rapid conversion of one polymorphic form to another governed by numerous factors and where there exists a significant difference amongst the pharmacological and toxicological properties of the drug.
U.S. Pat. No. 7,045,620 discloses purified polymorphic forms of rifaximin designated as Form α, Form β, and Form γ. It also discloses that the formation of these polymorphic forms could depend upon numerous factors, such as the presence of water within a crystallization solvent, the temperature at which the product is crystallized, and the amount of water present in the product at the end of the drying process. It further discloses that the presence of water in rifaximin in the solid state is reversible, such that the water absorption and/or release can take place under specific ambient conditions leading to a change in the polymorphic forms. Therefore, rifaximin is susceptible to transition from one form to another form even in the solid state, irrespective of the process involving the steps of dissolution and crystallization. This also stresses the fact that during the phase of preservation of the final rifaximin product, special care needs to be taken so that the ambient conditions do not change the water content of the product.
U.S. Pat. No. 8,193,196 discloses polymorphic forms of rifaximin designated as Form δ and Form ε. It further discloses that these two polymorphic forms show significant differences in terms of bioavailability leading to different pharmacological and toxicological behaviors. It also discloses the tendency of transformation of rifaximin polymorphic form δ to polymorphic form ε by a drying process.
U.S. Pat. No. 7,902,206 discloses rifaximin in polymorphic forms designated as Form α, Form β, or Form γ, wherein each form is free of any other polymorphic forms.
U.S. Pat. No. 7,915,275 discloses pharmaceutical compositions comprising an effective amount of a rifaximin polymorph and a pharmaceutically acceptable carrier. It further discloses that the compositions may contain any of the polymorphic forms such as Form α, Form β, or Form γ, or a mixture of more than one of these polymorphic forms. The mixture may be selected, for example, on the basis of desired amounts of systemic absorption, dissolution profile, and desired location in the digestive tract to be treated.
U.S. Application No. 2012/0059023 claims a method of preparing a pharmaceutical composition having a controlled systemic absorption of rifaximin, by combining two or more polymorphic forms of rifaximin such as Form α, Form β, and Form γ. It further discloses that the level of systemic rifaximin absorption can be modulated by administering distinct polymorphic forms of rifaximin.
A review of the art thus shows that rifaximin exists in various polymorphic forms with significant different pharmacological and toxicological behaviors, and with variable bioavailabilties. These polymorphic forms are susceptible to transformation from one form to another, even in a solid state at ambient conditions. The modification in the amounts of these different polymorphic forms in the finished pharmaceutical composition is highly critical as any variation in their amount during the shelf-life of the composition will directly affect the bioavailability of rifaximin in patients. Therefore, it is essential to prevent any modification of the polymorphic forms of rifaximin during the shelf-life of the finished pharmaceutical composition. The present inventors have now developed a pharmaceutical composition of rifaximin comprising a specific mixture of polymorphic forms of rifaximin which shows good stability in the relative polymorphic distribution ratio of these polymorphs, and which provides uniform therapeutic effect when administered to the patients.